Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer

  • Authors: Yuji Ikeda, Katsutoshi Oda, Osamu Hiraike-Wada, Takahiro Koso, Aki Miyasaka, Tomoko Kashiyama, Michihiro Tanikawa, Kenbun Sone, Kazunori Nagasaka, Daichi Maeda, Kei Kawana, Shunsuke Nakagawa, Masashi Fukayama, Osamu Tetsu, Tomoyuki Fujii, Tetsu Yano, Shiro Kozuma
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  • Published online on: Monday, June 3, 2013
  • Pages: 584-588
  • DOI: 10.3892/or.2013.2515

Abstract

Cyclin D1 is an important regulator of cell cycle progression. Phosphorylation of cyclin D1 at Thr286 by GSK3β triggers its nuclear export and cytoplasmic proteolysis via the 26S proteasome. Cyclin D1 overexpression is a common event in various types of human cancers; however, reports of mutations are extremely rare. We analyzed mutations of the cyclin D1 gene, CCND1, in 88 endometrial cancer tissue specimens and detected mutations in 2 cases (2.3%). Both were unreported mutations with substitution of threonine to isoleucine at codon 286 (T286I). These two tumors harbored coexisting mutations in K-ras, PIK3CA and/or PTEN and showed accumulation of cyclin D1 in the nucleus by immunohistochemistry. Furthermore, we analyzed the functions of mutant cyclin D1 (T286I) by luciferase assays, immunofluorescence, western blotting and clonogenic cell survival assays in HEK-293T cells. We found that exogenous mutant cyclin D1 (T286I) accumulated in the nuclei in HEK-293T cells, and that it inhibited the expression of pRb. Additionally, the number of colonies was increased by introduction of mutant cyclin D1 (T286I) compared to that of wild-type cyclin D1. In conclusion, we identified an unreported CCND1 mutation (T286I) in two endometrial cancers and revealed that the mutation was functional for inducing cell proliferation in human cells.
Journal Cover

August 2013
Volume 30 Issue 2

Print ISSN: 1021-335X
Online ISSN:1791-2431

2012 Impact Factor: 2.297
Ranked #36/196 Oncology
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APA
Ikeda, Y., Oda, K., Hiraike-Wada, O., Koso, T., Miyasaka, A., Kashiyama, T., Tanikawa, M., Sone, K., Nagasaka, K., Maeda, D., Kawana, K., Nakagawa, S., Fukayama, M., Tetsu, O., Fujii, T., Yano, T., & Kozuma, S. (2013). Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer. Oncology Reports, 30(2), 584-588.
MLA
Ikeda, Oda, Hiraike-Wada, Koso, Miyasaka, Kashiyama, Tanikawa, Sone, Nagasaka, Maeda, Kawana, Nakagawa, Fukayama, Tetsu, Fujii, Yano, and Shiro Kozuma. "Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer." Oncology Reports Oncology Reports 30.2 (2013): 584-588.
Chicago
Ikeda, Oda, Hiraike-Wada, Koso, Miyasaka, Kashiyama, Tanikawa, Sone, Nagasaka, Maeda, Kawana, Nakagawa, Fukayama, Tetsu, Fujii, Yano, and Shiro Kozuma. "Cyclin D1 harboring the T286I mutation promotes oncogenic activation in endometrial cancer." Oncology Reports Oncology Reports 30 no. 2 (2013): 584-588.